Amide-substituted 8-N-benzimidazoles, method for the production thereof, and use of the same as medicaments

ABSTRACT

The present invention comprises the use of amino-substituted 8-N-benzimidazoles compounds of formula I 
                         
wherein R3, R4-R5, R11 and R20-R21 are hereinafter defined which display a therapeutically utilizable blood sugar-lowering action. These compounds are intended to be particularly suitable in the treatment of diabetes.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of International Patent ApplicationNo. PCT/EP2006/002058 filed on Mar. 7, 2006 which is incorporated hereinby reference in its entirety which claims the benefit of priority ofGerman patent application Ser. No. 10/2005012874.2 filed on Mar. 19,2005.

FIELD OF THE INVENTION

The present invention relates generally to pharmaceutical compounds andcompositions comprising them for the treatment of metabolic blood serumdisorders and the physiological manifestations thereof. Morespecifically, the present invention relates to pharmaceutical compoundsand compositions comprising them for the treatment of metabolic bloodglucose disorders such as diabetes, hypoglycemia, hyperglycemia,hyperlipidemia, hypercholesterolemia and the like. More specifically,the present invention relates to amino-substituted 8-N-benzimidazolesand derivatives thereof for the treatment of blood glucose disorders.

BACKGROUND OF THE INVENTION

The present invention comprises the use of amino-substituted8-N-benzimidazoles and the physiologically compatible salts thereof forproducing a pharmaceutical composition for the treatment of blood sugardisorders. These compounds are particularly useful in the reduction ofblood sugar and, more specifically, in the therapeutic treatment ofdiabetes. The use of related or similar compounds has been known anddescribed in the prior art as follows. EP 1069124 describes2-benzimidazolylamines as ORL-1 receptor agonists. WO 97/12615 describesbenzimidazole derivatives as 15-LO inhibitors and WO 02/04425 describesstructurally similar virus polymerase inhibitors. WO 02/46168 describesbenzimidazole derivatives for treating Alzheimer's disease.

SUMMARY OF THE INVENTION

The present invention comprises the use of amino-substituted8-N-benzimidazoles compounds of formula I

wherein R3, R4-R5, R11 and R20-R21 are hereinafter defined which displaya therapeutically utilizable blood sugar-lowering action. Thesecompounds are intended to be particularly suitable in the treatment ofdiabetes.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to carboxamide derivative compounds of theformula I, below:

and their use in the treatment of blood sugar disorders wherein:

-   R20 is selected from the group consisting of H, (C₁-C₃)-alkyl, where    (C₁-C₃)-alkyl is optionally mono- or polysubstituted by CN, NO₂, SH,    OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    -   (C₄-C₆)-alkyl, where (C₄-C₆)-alkyl is optionally mono- or        polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,        (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    -   (C₇-C₁₀)-alkyl, (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl,        (C₂-C₁₀)-alkynyl, (C₆-C₁₀)-aryl, heterocycle,        (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl        (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle and S(O)₂-aryl, wherein        the alkyl, cycloalkyl, alkenyl, alkynyl, alkylene, aryl and        heterocycle groups are optionally mono- or polysubstituted by F,        Cl, Br, I, CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl        or S—(C₁-C₆)-alkyl;-   R21 is selected from the group consisting of (C₁-C₃)-alkyl, where    (C₁-C₃)-alkyl is optionally mono- or polysubstituted by CN, NO₂, SH,    OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    (C₄-C₆)-alkyl, where (C₄-C₆)-alkyl is optionally mono- or    polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,    (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl; (C₇-C₁₀)-alkyl,    (C₃-C₁₀)-cycloalkyl, (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl, heterocycle, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, where    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl (C₁-C₆)-alkylene-(C₆-C₁₀)-heterocycle    and S(O)₂-aryl, where the alkyl, cycloalkyl, alkenyl, alkynyl,    alkylene, aryl and heterocycle radicals are optionally mono- or    polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, CF₃,    (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl or S—(C₁-C₆)-alkyl;    excluding those definitions of the R21 substituent wherein it is    unsubstituted phenyl or unsubstituted benzyl;-   R3 is selected from the group consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₃)-alkyl, phenyl and    pyridyl, where the alkyl, cycloalkyl, cycloalkylalkyl, phenyl and    pyridyl radicals are optionally mono- or polysubstituted by CN, NO₂,    —CF₃, —OCF₃, OR12, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7,    CONR7R8 or OCONR7R8; (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl,    (C₆-C₁₀)-aryl, heterocycle and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, where    the alkenyl, alkynyl, aryl, heterocycle and alkylenearyl radicals    are optionally mono- or polysubstituted by F, Cl, Br, I, CN, NO₂,    OH, (C₁-C₆)-alkyl, —CF₃, —OCF₃, OR7, NR7R8, NR7CONR7R8, COR7, OCOR7,    OCOOR7, COOR7, CONR7R8 or OC(O)NR7R8;    excluding those definitions of R3 wherein it is an unsubstituted    phenyl or unsubstituted pyridyl, or substituted phenyl or    substituted pyridyl wherein each is substituted by F, Cl, Br, I, OH    or (C₁-C₆)-alkyl, from the R3 substituent;-   R7 and R8 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, —CF₃, (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl,    heterocycle, (C₁-C₆)-alkylene-CONR9R10, CONR9R10,    (C₁-C₆)-alkylene-COOR9, COOR9, COR9, (C₁-C₆)-alkylene-COR9,    (C₁-C₆)-alkylene-OR9, (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl and (C₁-C₄)-alkylene-heterocycle;-   R9 and R10 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-aryl,    heterocycle and (C₁-C₆)-alkylene-heterocycle;-   R12 is selected from the group consisting of (C₁-C₆)-alkyl, —CF₃,    (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl, heterocycle,    (C₁-C₆)-alkylene-CONR9R10, CONR9R10, (C₁-C₆)-alkylene-COOR9, COOR9,    COR9, (C₁-C₆)-alkylene-COR9, (C₁-C₆)-alkylene-OR9,    (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₂-C₄)-alkylene-(C₆-C₁₀)-aryl and (C₁-C₄)-alkylene-heterocycle;-   R4 and R5 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl and (C₃-C₈)-cycloalkyl, where (C₁-C₆)-alkyl and    (C₃-C₈)-cycloalkyl are optionally substituted by F, Cl, Br, I, CN,    aryl, heterocycle, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, OH,    O(C₁-C₆)-alkyl, (O)aryl, (O)heteroaryl, S(C₁-C₆)-alkyl,    S(O)(C₁-C₆)-alkyl and S(O)₂(C₁-C₆)-alkyl, wherein these alkyl groups    may in turn be substituted by F, Cl, Br or I;-   R11 is selected from the group consisting of H, F, Cl, Br, I,    (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂, NH(C₁-C₆)-alkyl,    NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ and O—(C₁-C₆)-alkyl, wherein    the alkyl groups may be mono- or poly-substituted by F, Cl, Br or I;-   n is 0, 1 or 2;    and the pharmaceutically acceptable salts thereof.

Preferably, the present invention comprises compounds of formula I inwhich one or more of the substituents are each defined as follows:

-   R20 is H;-   R21 is selected from the group consisting of (C₃-C₁₀)-cycloalkyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, phenyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-pyridyl, wherein the cycloalkyl, aryl and    pyridyl radicals may be mono- or polysubstituted by F, Cl, Br, I,    CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl and    S—(C₁-C₆)-alkyl;    excluding those definitions wherein R21 is an unsubstituted phenyl    or unsubstituted benzyl;-   R3 is selected from the group consisting of (C₁-C₆)-alkyl,    (C₃-C₇)-cycloalkyl, (C₃-C₇)-cycloalkyl-(C₁-C₃)-alkyl, phenyl,    pyridyl, where the alkyl, cycloalkyl, cycloalkylalkyl, phenyl and    pyridyl radicals are mono- or polysubstituted by CN, NO₂, —CF₃,    —OCF₃, OR12, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7, CONR7R8    and OCONR7R8; (C₂-C₁₀)-alkenyl, (C₂-C₁₀)-alkynyl, (C₆-C₁₀)-aryl,    heterocycle and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, wherein the alkenyl,    alkynyl, aryl, heterocycle and alkylene-aryl radicals may be mono-    or polysubstituted by F, Cl, Br, I, CN, NO₂, OH, (C₁-C₆)-alkyl,    —CF₃, —OCF₃, OR7, NR7R8, NR7CONR7R8, COR7, OCOR7, OCOOR7, COOR7,    CONR7R8 or OCONR7R8;    excluding those definitions wherein R3 is an unsubstituted phenyl or    an unsubstituted pyridyl, or a phenyl and pyridyl substituted by F,    Cl, Br, I, OH or (C₁-C₆)-alkyl;-   R7 and R8 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, —CF₃, (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl,    heterocycle, (C₁-C₆)-alkylene-CONR9R10, CONR9R10,    (C₁-C₆)-alkylene-COOR9, COOR9, COR9, (C₁-C₆)-alkylene-COR9,    (C₁-C₆)-alkylene-OR9, (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₁-C₄)-alkylene-(C₆-C₁₀)-aryl and (C₁-C₄)-alkylene-heterocycle;-   R9 and R10 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, —(C₆-C₁₀)-aryl,    heterocycle and (C₁-C₆)-alkylene-heterocycle;-   R12 is selected from the group consisting of (C₁-C₆)-alkyl, —CF₃,    (C₃-C₁₀)-cycloalkyl, (C₆-C₁₀)-aryl, heterocycle,    (C₁-C₆)-alkylene-CONR9R10, CONR9R10, (C₁-C₆)-alkylene-COOR9, COOR9,    COR9, (C₁-C₆)-alkylene-COR9, (C₁-C₆)-alkylene-OR9,    (C₁-C₆)-alkylene-NR9R10, (C₁-C₆)-alkylene-SR9,    (C₁-C₆)-alkylene-S(O)R9, (C₁-C₆)-alkylene-S(O)₂R9, S(O)R9, S(O)₂R9,    (C₂-C₄)-alkylene-(C₆-C₁₀)-aryl or (C₁-C₄)-alkylene-heterocycle;-   R4 and R5 are each independently selected from the group consisting    of H, (C₁-C₆)-alkyl or (C₃-C₈)-cycloalkyl, where (C₁-C₆)-alkyl or    (C₃-C₈)-cycloalkyl may be substituted by F, Cl, Br, I, CN, aryl,    heterocycle, NH₂, NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, OH,    O(C₁-C₆)-alkyl, O-aryl, O-heteroaryl, S(C₁-C₆)-alkyl,    S(O)(C₁-C₆)-alkyl or S(O)₂(C₁-C₆)-alkyl, where these alkyl groups    may in turn be substituted by F, Cl, Br or I;-   R11 is selected from the group consisting of H, F, Cl, Br, I,    (C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂, NH(C₁-C₆)-alkyl,    NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ and O—(C₁-C₆)-alkyl, where    the alkyl groups may be mono- or polysubstituted by F, Cl, Br or I;-   n is 0, 1 or 2;    and the pharmaceutically acceptable salts thereof.

More preferably, the present invention comprises compounds of formula Iin which one or more of the substituents are each more specificallydefined as follows:

-   R20 is H;-   R21 is selected from the group consisting of (C₃-C₁₀)-cycloalkyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, phenyl,    (C₁-C₆)-alkylene-(C₆-C₁₀)-pyridyl, where the cycloalkyl, aryl and    pyridyl radicals may be mono- or polysubstituted by F, Cl, Br, I,    CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl and    S—(C₁-C₆)-alkyl;    excluding those definitions of R21 wherein it is an unsubstituted    phenyl or unsubstituted benzyl;-   R3 is independently selected from the group consisting of    (C₂-C₁₀)-alkenyl or (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, where the    alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl radicals may be mono- or    polysubstituted by F, Cl, Br;-   R4 and, R5 are each H;-   n is 0;    and the pharmaceutically acceptable salts thereof.

Most preferably, the present invention comprises compounds of formula Iin which one or more of the substituents are each more specificallydefined as follows:

-   R20 is H;-   R21 is (C₃-C₁₀)-cycloalkyl, benzyl, pyridyl, phenyl, where the    alkyl, cycloalkyl and benzyl radicals may be mono- or    polysubstituted by F, Cl, Br, I, CN, NO₂, SH, OH, (C₁-C₆)-alkyl,    O—(C₁-C₆)-alkyl and S—(C₁-C₆)-alkyl;    excluding the definitions of the R21 substituent wherein it is an    unsubstituted phenyl and unsubstituted benzyl;-   R3 is independently selected from the group consisting of    (C₂-C₁₀)-alkenyl or (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, where the    alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl radicals may be mono- or    polysubstituted by F, Cl, Br;-   R4, R5 are each H;-   n is 0;    and the pharmaceutically acceptable salts thereof.

The present invention also comprises compounds of formula I in the formof their racemates, racemic mixtures, pure enantiomers, theirdiastereomers and mixtures thereof.

When the R-groups or substituents can occur more than once in thecompounds of formula I, they may all each independently have thedefinitions specified and be the same or different.

Owing to their higher water solubility, pharmaceutically acceptablesalts are particularly suitable for medical applications compared to thestarting or base compounds. These salts must have a pharmaceuticallyacceptable anion or cation. Suitable pharmaceutically acceptable acidaddition salts of the inventive compounds are salts of inorganic acidssuch as hydrochloric acid, hydrobromic acid, phosphoric acid,metaphosphoric acid, nitric acid and sulfuric acid, and organic acids,for example acetic acid, benzenesulfonic acid, benzoic acid, citricacid, ethanesulfonic acid, fumaric acid, gluconic acid, glycolic acid,isethionic acid, lactic acid, lactobionic acid, maleic acid, malic acid,methanesulfonic acid, succinic acid, p-toluenesulfonic acid and tartaricacid. Suitable pharmaceutically acceptable basic salts are ammoniumsalts, alkali metal salts (such as sodium and potassium salts) andalkaline earth metal salts (such as magnesium and calcium salts) andsalts of trometamol (2-amino-2-hydroxymethyl-1,3-propanediol),diethanolamine, lysine or ethylenediamine.

Salts with a pharmaceutically unacceptable anion, for exampletrifluoroacetate, are likewise included in the scope of the invention asuseful intermediates for the preparation or purification ofpharmaceutically acceptable salts and/or for the use in non-therapeutic,for example in vitro, applications.

The term “physiologically functional derivative” used here refers to anyphysiologically compatible derivative of an inventive compound of theformula I, for example an ester which, on administration to a mammal,for example the human, is capable (directly or indirectly) of forming acompound of the formula I or an active metabolite thereof.

The physiologically functional derivatives also include prodrugs of theinventive compounds. Such prodrugs can be metabolized in vivo to give aninventive compound. These prodrugs may or may not themselves be active.

The inventive compounds may also be present in various polymorphicforms, for example as amorphous and crystalline polymorphic forms. Allpolymorphic forms of the inventive compounds are included within thescope of the invention and are a further aspect of the invention.

Hereinafter, all references to “compound(s) of the formula (I)” relateto compound(s) of the formula I as described above, and also theirsalts, solvates and physiologically functional derivatives as describedherein.

An alkyl substituent means a straight-chain or branched hydrocarbonchain having one or more carbons, for example methyl, ethyl, isopropyl,tert-butyl, hexyl and so on.

The alkyl radicals may be mono- or poly-substituted by suitable groups,for example: F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl,O—CO—(C₁-C₆)-aryl, O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂,SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl,SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂; C(═NH)(NH₂), NH₂,NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, NH—CO—(C₁-C₆)-alkyl,NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl, NH—CO-heterocycle, NH—COO-aryl,NH—COO-heterocycle, NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl,NH—CO—NH-heterocycle, N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,N((C₁-C₆)-alkyl)-COO-heterocycle, N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl),N((C₁-C₆)-alkyl)-CO—NH-aryl, N((C₁-C₆)-alkyl)-CO—NH-heterocycle,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂, N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl andO—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical orheterocyclic radical may be mono- to trisubstituted by F, Cl, Br, I, OH,CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl orCONH₂.

An alkenyl substituent means a straight-chain or branched hydrocarbonchain having two or more carbons and one or more double bonds, forexample vinyl, allyl, pentenyl, 2-methyl-but-2-en-4-yl.

The alkenyl substituent may be mono- or polysubstituted by suitablegroups, for example:

-   F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,    CONH(C₁-C₆)alkyl, CON [(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-aryl, O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂,    SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,    S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl,    SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl,    SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,    SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,    SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl    radical or heterocyclic radical may be up to disubstituted by F, Cl,    Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;-   C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,    NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,    NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,    N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,    N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,    N((C₁-C₆)-alkyl)-COO-heterocycle,    N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,    N((C₁-C₆)-alkyl)-CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,    N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,    N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,    N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,    N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,    N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),    N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,    N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂,    N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,    N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl and    O—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical    or heterocyclic radical may be mono- to trisubstituted by F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl    or CONH₂.

An alkynyl substituent means a straight-chain or branched hydrocarbonchain having two or more carbons and one or more triple bonds, forexample ethynyl, propynyl, butynyl, hexynyl.

The alkynyl radicals may be mono- or polysubstituted by suitable groups,for example: F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl,CONH₂, CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl,(C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl,O—CO—(C₁-C₆)-aryl, O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂,SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl,SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl,SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl radical orheterocyclic radical may be up to disubstituted by F, Cl, Br, OH, CF₃,NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;

-   C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,    NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,    NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,    N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,    N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,    N((C₁-C₆)-alkyl)-COO-heterocycle,    N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,    N((C₁-C₆)-alkyl)-CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,    N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,    N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,    N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,    N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,    N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),    N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,    N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂,    N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,    N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl and    O—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical    or heterocyclic radical may be mono- to trisubstituted by F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl    or CONH₂.

An aryl substituent is a phenyl, naphthyl, biphenyl, tetrahydronaphthyl,alpha- or beta-tetralonyl, indanyl or indan-1-onyl radical.

The aryl substituents may be mono- or polysubstituted by suitablegroups, for example:

-   F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,    CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-aryl, O—CO—(C₁-C₆)-heterocycle;-   PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,    S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,    SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,    SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,    SO₂—NH(CH₂)_(r)-aryl, SO₂—NH(CH₂)_(r)-heterocycle,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(r)-aryl)₂,    SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl    radical or heterocyclic radical may be up to disubstituted by F, Cl,    Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;-   C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,    NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,    NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,    N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,    N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,    N((C₁-C₆)-alkyl)-COO-heterocycle,    N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,    N((C₁-C₆)-alkyl)-CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,    N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,    N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,    N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,    N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,    N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),    N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,    N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂,    N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,    N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl and    O—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical    or heterocyclic radical may be mono- to trisubstituted by F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl    or CONH₂.

A cycloalkyl substituent means a ring system which comprises one or morerings and is present in saturated or partially unsaturated form (withone or two double bonds), and is formed exclusively from carbon atoms,for example cyclopropyl, cyclopentyl, cyclopentenyl, cyclohexyl oradamantyl.

The cycloalkyl radicals may be mono- or polysubstituted by suitablegroups, for example:

-   F, Cl, Br, I, CF₃, NO₂, N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂,    CONH(C₁-C₆)alkyl, CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl,    (C₂-C₆)-alkynyl, O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl,    O—CO—(C₁-C₆)-aryl, O—CO—(C₁-C₆)-heterocycle; PO₃H₂, SO₃H, SO₂—NH₂,    SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂, S—(C₁-C₆)-alkyl,    S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle, SO—(C₁-C₆)-alkyl,    SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle, SO₂—(C₁-C₆)-alkyl,    SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle, SO₂—NH(CH₂)_(n)-aryl,    SO₂—NH(CH₂)_(n)-heterocycle, SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,    SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl    radical or heterocyclic radical may be up to disubstituted by F, Cl,    Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;-   C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,    NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,    NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,    N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,    N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,    N((C₁-C₆)-alkyl)-COO-heterocycle,    N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,    N((C₁-C₆)-alkyl)-CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,    N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,    N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,    N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,    N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,    N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),    N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,    N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂,    N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,    N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl and    O—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl radical    or heterocyclic radical may be mono- to trisubstituted by F, Cl, Br,    I, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl    or CONH₂.

Heterocycle substituents or groups or “heterocyclic substituent ringsystems mean those groups which, apart from carbon, also containheteroatoms, for example nitrogen, oxygen or sulfur. This definitionalso includes ring systems in which the heterocycle or the heterocyclicradical is fused to benzene rings. The heterocycle or the heterocyclicgroup may be aromatic, saturated aliphatic or partially unsaturatedaliphatic.

Suitable heterocycle substituents or “heterocyclic groups” areacridinyl, azocinyl, benzimidazolyl, benzofuryl, benzothienyl,benzothiophenyl, benzoxazolyl, benzthiazolyl, benztriazolyl,benztetrazolyl, benzisoxazolyl, benzisothiazolyl, benzimidazalinyl,carbazolyl, 4aH-carbazolyl, carbolinyl, quinazolinyl, quinolinyl,4H-quinolizinyl, quinoxalinyl, quinuclidinyl, chromanyl, chromenyl,cinnolinyl, decahydroquinolinyl, 2H,6H-1,5,2-dithiazinyl,dihydrofuro[2,3-b]-tetrahydrofuran, furyl, furazanyl, imidazolidinyl,imidazolinyl, imidazolyl, 1H-indazolyl, indolinyl, indolizinyl, indolyl,3H-indolyl, isobenzofuranyl, isochromanyl, isoindazolyl, isoindolinyl,isoindolyl, isoquinolinyl (benzimidazolyl), isothiazolyl, isoxazolyl,morpholinyl, naphthyridinyl, octahydroisoquinolinyl, oxadiazolyl,1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl, oxazolidinyl, pyrimidinyl,phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl,phenoxathiinyl, phenoxazinyl, phthalazinyl, piperazinyl, piperidinyl,pteridinyl, purynyl, pyranyl, pyrazinyl, pyroazolidinyl, pyrazolinyl,pyrazolyl, pyridazinyl, pyridooxazole, pyridoimidazole, pyridothiazole,pyridinyl, pyridyl, pyrimidinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl,pyrrolyl, tetrahydrofuranyl, tetrahydroisoquinolinyl,tetrahydroquinolinyl, 6H-1,2,5-thiadazinyl, thiazolyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl,1,3,4-thiadiazolyl, thienyl, triazolyl, tetrazolyl and xanthenyl.

Pyridyl is 2-, 3- or 4-pyridyl. Thienyl is 2- or 3-thienyl. Furyl is 2-or 3-furyl.

Also included are the corresponding N-oxides of these compounds, i.e.,for example, 1-oxy-2-, -3- or -4-pyridyl.

Also included are mono- or polybenzo fused derivatives of theseheterocyclic groups.

The heterocyclic rings or heterocyclic radicals may be mono- orpolysubstituted by suitable groups, for example: F, Cl, Br, I, CF₃, NO₂,N₃, CN, COOH, COO(C₁-C₆)alkyl, CONH₂, CONH(C₁-C₆)alkyl,CON[(C₁-C₆)alkyl]₂, cycloalkyl, (C₂-C₆)-alkenyl, (C₂-C₆)-alkynyl,O—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-alkyl, O—CO—(C₁-C₆)-aryl,O—CO—(C₁-C₆)-heterocycle;

-   PO₃H₂, SO₃H, SO₂—NH₂, SO₂NH(C₁-C₆)-alkyl, SO₂N[(C₁-C₆)-alkyl]₂,    S—(C₁-C₆)-alkyl, S—(CH₂)_(n)-aryl, S—(CH₂)_(n)-heterocycle,    SO—(C₁-C₆)-alkyl, SO—(CH₂)_(n)-aryl, SO—(CH₂)_(n)-heterocycle,    SO₂—(C₁-C₆)-alkyl, SO₂—(CH₂)_(n)-aryl, SO₂—(CH₂)_(n)-heterocycle,    SO₂—NH(CH₂)_(n)-aryl, SO₂—NH(CH₂)_(n)-heterocycle,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-aryl,    SO₂—N((C₁-C₆)-alkyl)(CH₂)_(n)-heterocycle, SO₂—N((CH₂)_(n)-aryl)₂,    SO₂—N((CH₂)_(n)-heterocycle)₂ where n may be 0-6 and the aryl    radical or heterocyclic radical may be up to disubstituted by F, Cl,    Br, OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl or NH₂;-   C(═NH)(NH₂), NH₂, NH—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂,    NH—CO—(C₁-C₆)-alkyl, NH—COO—(C₁-C₆)-alkyl, NH—CO-aryl,    NH—CO-heterocycle, NH—COO-aryl, NH—COO-heterocycle,    NH—CO—NH—(C₁-C₆)-alkyl, NH—CO—NH-aryl, NH—CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—(C₁-C₆)-alkyl,    N((C₁-C₆)-alkyl)-COO—(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)-CO-aryl,    N((C₁-C₆)-alkyl)-CO-heterocycle, N((C₁-C₆)-alkyl)-COO-aryl,    N((C₁-C₆)-alkyl)-COO-heterocycle,    N((C₁-C₆)-alkyl)-CO—NH—(C₁-C₆)-alkyl), N((C₁-C₆)-alkyl)-CO—NH-aryl,    N((C₁-C₆)-alkyl)-CO—NH-heterocycle,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)₂,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-aryl,    N((C₁-C₆)-alkyl)-CO—N((C₁-C₆)-alkyl)-heterocycle,    N((C₁-C₆)-alkyl)-CO—N-(aryl)₂, N((C₁-C₆)-alkyl)-CO—N-(heterocycle)₂,    N(aryl)-CO—(C₁-C₆)-alkyl, N(heterocycle)-CO—(C₁-C₆)-alkyl,    N(aryl)-COO—(C₁-C₆)-alkyl, N(heterocycle)-COO—(C₁-C₆)-alkyl,    N(aryl)-CO-aryl, N(heterocycle)-CO-aryl, N(aryl)-COO-aryl,    N(heterocycle)-COO-aryl, N(aryl)-CO—NH—(C₁-C₆)-alkyl),    N(heterocycle)-CO—NH—(C₁-C₆)-alkyl), N(aryl)-CO—NH-aryl,    N(heterocycle)-CO—NH-aryl, N(aryl)-CO—N((C₁-C₆)-alkyl)₂,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)₂,    N(aryl)-CO—N((C₁-C₆)-alkyl)-aryl,    N(heterocycle)-CO—N((C₁-C₆)-alkyl)-aryl, N(aryl)-CO—N-(aryl)₂,    N(heterocycle)-CO—N-(aryl)₂, aryl, O—(CH₂)_(n)-aryl and    O—(CH₂)_(n)-heterocycle, where n may be 0-6, where the aryl group or    heterocyclic group may be mono- to trisubstituted by F, Cl, Br, I,    OH, CF₃, NO₂, CN, OCF₃, O—(C₁-C₆)-alkyl, (C₁-C₆)-alkyl, NH₂,    NH(C₁-C₆)-alkyl, N((C₁-C₆)-alkyl)₂, SO₂—CH₃, COOH, COO—(C₁-C₆)-alkyl    or CONH₂.

The compound(s) of the formula (I) may also be administered incombination with additional active ingredients.

The amount of a compound of the formula I which is required in order toachieve the desired biological effect is dependent upon a series offactors, for example the specific compound selected, the intended use,the mode of administration and the clinical condition of the patient.The daily dose is generally in the range from 0.3 mg to 100 mg(typically from 3 mg to 50 mg) per day per kilogram of bodyweight, forexample 3-10 mg/kg/day. An intravenous dose may, for example, be in therange from 0.3 mg to 1.0 mg/kg and may suitably be administered as aninfusion of from 10 ng to 100 ng per kilogram per minute. Suitableinfusion solutions for these purposes may, for example, contain from 0.1ng to 10 mg, typically from 1 ng to 10 mg, per milliliter. Single dosesmay contain, for example, from 1 mg to 10 g of the active ingredient.Ampoules for injections may therefore contain, for example, from 1 mg to100 mg, and single dose formulations which can be administered orally,for example tablets or capsules, may contain, for example, from 1.0 to1000 mg, typically from 10 to 600 mg. The compounds of the formula I maybe used for therapy of the afore-mentioned conditions as the compoundsthemselves, although they are preferably in the form of a pharmaceuticalcomposition with an acceptable carrier. The carrier of course has to beacceptable, in the sense that it is compatible with the otherconstituents of the composition and is not damaging to the health of thepatient. The carrier may be a solid or a liquid or both and ispreferably formulated with the compound as a single dose, for example asa tablet, which may contain from 0.05 to 95% by weight of the activeingredient. Further pharmaceutically active substances may likewise bepresent, including further compounds of the formula I. The inventivepharmaceutical compositions may be produced by one of the knownpharmaceutical methods which consist essentially in mixing theconstituents with pharmacologically acceptable carriers and/orexcipients.

The pharmaceutical compositions of the present invention are those whichare suitable for oral, rectal, topical, peroral (for example sublingual)and parenteral (for example sub-cutaneous, intra-muscular, intra-dermalor intra-venous) administration, although the most suitable mode ofadministration depends in each individual case on the nature andseverity of the condition to be treated and on the type of the compoundof the formula I used in each case. Coated formulations and coatedslow-release formulations are also encompassed by the scope of theinvention. Preference is given to acid- and gastric fluid-resistantformulations. Suitable gastric fluid-resistant coatings includecellulose acetate phthalate, polyvinyl acetate phthalate,hydroxypropylmethylcellulose phthalate and anionic polymers ofmethacrylic acid and methyl methacrylate.

Suitable pharmaceutical preparations for oral administration may be inthe form of separate units, for example capsules, cachets, lozenges ortablets, each of which contains a certain amount of the compound of theformula I; as powder or granules; as solution or suspension in anaqueous or non-aqueous liquid; or as an oil-in-water or water-in-oilemulsion. These compositions may, as already mentioned, be prepared byany suitable pharmaceutical method which includes a step in which theactive ingredient and the carrier (which may consist of one or moreadditional constituents) are brought into contact. In general, thecompositions are prepared by uniform and homogeneous mixing of theactive ingredient with a liquid carrier and/or finely divided solidcarrier, after which the product is shaped if necessary. For example, atablet can thus be produced by compressing or shaping a powder orgranules of the compound, optionally with one or more additionalconstituents. Compressed tablets can be prepared by tableting thecompound in free-flowing form, for example a powder or granules,optionally mixed with a binder, lubricant, inert diluent and/or one (ormore) surfactants/dispersants in a suitable machine. Shaped tablets canbe prepared by shaping the pulverulent compound moistened with an inertliquid diluent in a suitable machine.

Pharmaceutical compositions which are suitable for peroral (sublingual)administration include lozenges which contain a compound of the formulaI with a flavoring, customarily sucrose, and gum arabic or tragacanth,and pastilles which include the compound in an inert base, such asgelatin and glycerol or sucrose and gum arabic.

Suitable pharmaceutical compositions for parenteral administrationinclude preferably sterile aqueous preparations of a compound of theformula I which are preferably isotonic with the blood of the intendedrecipient. These preparations are preferably administered intravenously,although the administration may also be subcutaneous, intramuscular orintradermal as an injection. These preparations can preferably beproduced by mixing the compound with water and making the solutionobtained sterile and isotonic with the blood. Injectable compositionsaccording to the invention generally contain from 0.1 to 5% by weight ofthe active compound.

Suitable pharmaceutical compositions for rectal administration arepreferably in the form of single dose suppositories. These can beprepared by mixing a compound of the formula I with one or moreconventional solid carriers, for example cocoa butter, and shaping theresulting mixture.

Suitable pharmaceutical compositions for topical application on the skinare preferably in the form of an ointment, cream, lotion, paste, spray,aerosol or oil. Useful carriers include petroleum jelly, lanolin,polyethylene glycols, alcohols and combinations of two or more of thesesubstances. The active ingredient is generally present in aconcentration of from 0.1 to 15% by weight of the composition,preferably from 0.5 to 2%.

Transdermal administration is also possible. Suitable pharmaceuticalcompositions for transdermal applications may be in the form of singleplasters which are suitable for long-term close contact with theepidermis of the patient. Such plasters suitably contain the activeingredient in an optionally buffered aqueous solution, dissolved and/ordispersed in an adhesive or dispersed in a polymer. A suitable activeingredient concentration is from approx. 1% to 35%, preferably fromapprox. 3% to 15%. A particular means of releasing the active ingredientmay be by electrotransport or iontophoresis, as described, for example,in Pharmaceutical Research, 2(6): 318 (1986).

The compounds of the formula I may be administered alone or else also incombination with one or more additional active ingredients. Other usefulactive ingredients for combination products are as follows:

One or more anti-diabetic compounds disclosed in the Rote Liste 2001,chapter 12 may also be incorporated as a second additional active in thecompositions of the present invention. They can be combined with theinventive compounds of the formula I, in particular for synergisticenhancement of action. The active ingredient combination can beadministered either by separately administering the active ingredientsto the patient or in the form of combination products in which aplurality of active ingredients are present in one pharmaceuticalpreparation. Most of the active ingredients listed hereinbelow aredisclosed in USP Dictionary of USAN and International Drug Names, USPharmacopeia, Rockville 2001.

Anti-diabetics include insulin and insulin derivatives, for exampleLantus® (see www.lantus.com) or Apidra®, fast-acting insulins (see U.S.Pat. No. 6,221,633), GLP-1 derivatives, for example those disclosed inWO 98/08871 of Novo Nordisk A/S, and orally active hypoglycemic activeingredients.

The orally active hypoglycemic active ingredients preferably includesulfonylureas, biguanidines, meglitinides, oxadiazolidinediones,thiazolidinediones, glucosidase inhibitors, glucagon antagonists, GLP-1agonists, potassium channel openers, for example those disclosed in WO97/26265 and WO 99/03861 of Novo Nordisk A/S, insulin sensitizers,inhibitors of liver enzymes which are involved in the stimulation ofgluconeogenesis and/or glycogenolysis, modulators of glucose uptake,compounds which alter lipid metabolism such as antihyperlipidemic activeingredients and antilipidemic active ingredients, compounds which reducefood intake, PPAR and PXR agonists and active ingredients which act onthe ATP-dependent potassium channel of the beta cells (PPAR=peroxisomeproliferator-activated receptor, PXR=pregnane X receptor, ATP=adenosinetriphosphate).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an HMG-CoA reductase inhibitor such assimvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin,cerivastatin, rosuvastatin (HMG-CoA=3-hydroxy-3-methylglutaryl coenzymeA).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a cholesterol absorption inhibitor, forexample, ezetimibe, tiqueside, pamaqueside, or with a compound asdescribed in PCT/EP 2004/00269, WO 2004/000804, WO 2004/000803, WO2004/000805, EP 0114531, U.S. Pat. No. 6,498,156.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a PPAR gamma agonist, for example,rosiglitazone, pioglitazone, JTT-501, GI 262570.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with PPAR alpha agonist, for example, GW9578, GW 7647.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a mixed PPAR alpha/gamma agonist, forexample, GW 1536, AVE 8042, AVE 8134, AVE 0847, or as described in WO00/64888, WO 00/64876, DE10142734.4.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a fibrate, for example fenofibrate,clofibrate, bezafibrate.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an MTP inhibitor, for exampleimplitapide, BMS-201038, R-103757 (MTP=microsomal triglyceride transferprotein).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with bile acid absorption inhibitor (see,for example, U.S. Pat. No. 6,245,744 or U.S. Pat. No. 6,221,897), forexample HMR 1741.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a CETP inhibitor, for example JTT-705(CETP=cholesteryl ester transfer protein).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a polymeric bile acid adsorber, forexample cholestyramine, colesevelam.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an LDL receptor inducer (see U.S. Pat.No. 6,342,512), for example HMR1171, HMR1586 (LDL=low density lipids).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ACAT inhibitor, for exampleavasimibe (ACAT=acyl coenzyme A: cholesterol acyl transferase).

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an antioxidant, for example OPC-14117.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein lipase inhibitor, forexample NO-1886.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with an ATP citrate lyase inhibitor, forexample SB-204990.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a squalene synthetase inhibitor, forexample BMS-188494.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipoprotein(a) antagonist, forexample Cl-1027 or nicotinic acid.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with a lipase inhibitor, for exampleorlistat.

In one embodiment of the invention, the compounds of the formula I areadministered in combination with insulin.

In one embodiment, the compounds of the formula I are administered incombination with a sulfonylurea, for example tolbutamide, glibenclamide,glipizide or glimepiride.

In one embodiment, the compounds of the formula I are administered incombination with a biguanide, for example metformin.

In yet another embodiment, the compounds of the formula I areadministered in combination with a meglitinide, for example repaglinide.

In one embodiment, the compounds of the formula I are administered incombination with a thiazolidinedione, for example troglitazone,ciglitazone, pioglitazone, rosiglitazone or the compounds disclosed inWO 97/41097 of Dr. Reddy's Research Foundation, in particular5-[[4-[(3,4-dihydro-3-methyl-4-oxo-2-quinazolinylmethoxy]-phenyl]methyl]-2,4-thiazolidinedione.

In one embodiment, the compounds of the formula I are administered incombination with an α-glucosidase inhibitor, for example miglitol oracarbose.

In one embodiment, the compounds of the formula I are administered incombination with adenosine A1 agonists, for example those which aredescribed in WO 2004/003002.

In one embodiment, the compounds of the formula I are administered incombination with an active ingredient which acts on the ATP-dependentpotassium channel of the beta cells, for example tolbutamide,glibenclamide, glipizide, glimepiride or repaglinide. In one embodiment,the compounds of the formula I are administered in combination with morethan one of the abovementioned compounds, for example in combinationwith a sulfonylurea and mefformin, a sulfonylurea and acarbose,repaglinide and mefformin, insulin and a sulfonylurea, insulin andmefformin, insulin and troglitazone, insulin and lovastatin, etc.

In a further embodiment, the compounds of the formula I are administeredin combination with CART modulators (see “Cocaine-amphetamine-regulatedtranscript influences energy metabolism, anxiety and gastric emptying inmice” Asakawa, A, et al., M.: Hormone and Metabolic Research (2001),33(9), 554-558), NPY antagonists (NPY=neuropeptide Y), e.g.naphthalene-1-sulfonic acid{4-[(4-aminoquinazolin-2-ylamino)methyl]cyclohexylmethyl}amidehydrochloride (CGP 71683A)), MC4 agonists (MC4=melanocortin 4 receptor,e.g. 1-amino-1,2,3,4-tetrahydronaphthalene-2-carboxylic acid[2-(3a-benzyl-2-methyl-3-oxo-2,3,3a,4,6,7-hexahydropyrazolo[4,3-c]pyridin-5-yl)-1-(4-chlorophenyl)-2-oxo-ethyl]amide;(WO 01/91752)), orexin antagonists (e.g.1-(2-methylbenzoxazol-6-yl)-3-[1,5]naphthyridin-4-ylurea; hydrochloride(SB-334867-A)), H3 agonists (H3=histamine receptor, e.g.3-cyclohexyl-1-(4,4-dimethyl-1,4,6,7-tetrahydroimidazo[4,5-c]pyridin-5-yl)propan-1-oneoxalic acid salt (WO 00/63208)); TNF agonists (TNF=tumor necrosisfactor), CRF antagonists (CRF=corticotropin releasing factor, e.g.[2-methyl-9-(2,4,6-trimethylphenyl)-9H-1,3,9-triazafluoren-4-yl]dipropylamine(WO 00/66585)), CRF BP antagonists (CRF BP=corticotropin releasingfactor binding protein, e.g. urocortin), urocortin agonists, β3 agonists(e.g.1-(4-chloro-3-methanesulfonylmethylphenyl)-2-[2-(2,3-dimethyl-1H-indol-6-yloxy)ethylamino]ethanolhydrochloride (WO 01/83451)), CB1 (cannabinoid receptor 1) receptorantagonists (e.g. rimonabant or the active ingredients specified in WO02/28346), MSH (melanocyte-stimulating hormone) agonists, CCK-A(CCK-A=cholecystokinin-A) agonists (e.g.{2-[4-(4-chloro-2,5-dimethoxyphenyl)-5-(2-cyclohexylethyl)thiazol-2-ylcarbamoyl]-5,7-dimethylindol-1-yl}aceticacid trifluoroacetic acid salt (WO 99/15525)), serotonin reuptakeinhibitors (e.g. dexfenfluramine), mixed serotoninergic andnoradrenergic compounds (e.g. WO 00/71549), 5HT agonists (serotoninmimetics) e.g. 1-(3-ethylbenzofuran-7-yl)piperazine oxalic acid salt (WO01/09111), bombesin agonists, galanin antagonists, growth hormone (e.g.human growth hormone), growth hormone-releasing compounds(6-benzyloxy-1-(2-diisopropylaminoethyl-carbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester (WO 01/85695)), TRH agonists (TRH=TSH releasinghormone; TSH=thyroid-stimulating hormone; thyrotropin), see, forexample, EP 0 462 884, uncoupling protein 2 or 3 modulators, leptinagonists (see, for example, Lee, Daniel W.; Leinung, Matthew C.;Rozhavskaya-Arena, Marina; Grasso, Patricia. Leptin agonists as apotential approach to the treatment of obesity. Drugs of the Future(2001), 26(9), 873-881), DA agonists (DA=dopamine autoreceptor, forexample bromocriptine, doprexin), lipase/amylase inhibitors (e.g. WO00/40569), PPAR modulators (e.g. WO 00/78312), RXR(RXR=retinoid Xreceptor) modulators or TR-β agonists.

In one embodiment of the invention, the other active ingredient isleptin; see, for example, “Perspectives in the therapeutic use ofleptin”, Salvador, Javier; Gomez-Ambrosi, Javier; Fruhbeck, Gema, ExpertOpinion on Pharmacotherapy (2001), 2(10), 1615-1622.

In one embodiment, the other active ingredient is dexamphetamine oramphetamine.

In one embodiment, the other active ingredient is fenfluramine ordexfenfluramine.

In yet another embodiment, the other active ingredient is sibutramine.

In one embodiment, the other active ingredient is orlistat.

In one embodiment, the other active ingredient is mazindol orphentermine.

In another embodiment, the other active ingredient is rimonabant.

In one embodiment, the compounds of the formula I are administered incombination with dietary fiber materials, preferably insoluble dietaryfiber materials (see, for example, Carob/Caromax® (Zunft H J; et al.,Carob pulp preparation for treatment of hypercholesterolemia, ADVANCESIN THERAPY (2001 September-October), 18(5), 230-6.); Caromax is acarob-containing product supplied by Nutrinova, Nutrition Specialties &Food Ingredients GmbH, Industriepark Höchst, 65926 Frankfurt/Main)).Combination with Caromax® is possible in one preparation or by separateadministration of compounds of the formula I and Caromax®. Caromax® canalso be administered in the form of foodstuffs, for example, in bakeryproducts or muesli bars.

It will be appreciated that any suitable combination of the compoundsaccording to the invention with one or more of the abovementionedcompounds and optionally one or more further pharmacologically activesubstances is regarded as being covered by the scope of protection ofthe present invention.

The compounds of formula I of the present invention can be prepared byreacting suitable starting materials of the formula II in which X is aleaving group, such as chlorine, bromine, iodine, sulfonyloxy, sulfinylor sulfoxyl, and R30 is an ester or an amide, with a compound of theformula IV optionally in the presence of suitable bases and in suitablesolvents.

In the cases where R4 and R5 are simultaneously hydrogen, it may beappropriate to use the radical IV in a form protected on the nitrogenfunction and to detach the protecting group again on completion ofreaction with 11. Such suitable protecting groups and the processes fortheir introduction and detachment are known (see: Theodora W. Greene andPeter G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition,John Wiley & Sons, Inc., New York, 1999).

The halogen compounds of the formula II can be obtained by knownprocesses, for example by halogenating the corresponding H, hydroxyl orthio compound (formula II, X═H, OH or SH). Suitable halogenating agentsmay, by way of example, be halogens such as chlorine and bromine,N-bromosuccinimide, phosphorus pentachloride or phosphorus oxychloride.

The synthesis of compounds of the formula II is described in theliterature. They may be prepared, for example, by condensing substituteddiaminobenzene derivatives with aldehydes in the presence of anoxidizing agent (for example atmospheric oxygen, oxygen, iodine, oxone,quinones, peroxides, etc.), or alternatively with carboxylic acids,nitrites or amides, without or in the presence of a catalyst.

The amines IV can be synthesized by processes known from the literature.

Some derivatives of the formula IV, for example piperidin-3-ylamines arecommercially available.

The esters or amides CO—R30 can be converted to the amides CO—NR20R21 bymethods known from the literature.

The tabulated examples listed below are provided to better illustratemethods for practicing the present invention as disclosed herein. Theexamples are provided to better describe and more specifically set forththe compounds, processes and methods of the present invention ascontemplated herein. However, it is to be recognized that they are forillustrative purposes only, and should not be interpreted as limitingthe spirit and scope of the invention as later recited by the claimsthat follow.

TABLE 1 I

Binding site C═O— Ex. A No. NR20R21 R20 R21 R3 NR4R5 n R11 1 A003394 6 H4-Cl-Benzyl- 4-F-Benzyi 3-R—NH₂ × HCl 0 — 933A 2 A003394 6 H3-CF₃-Benzyl- 4-F-Benzyl 3-R—NH₂ × HCl 0 — 934A 3 A003394 6 H2-Cl-Benzyl- 4-F-Benzyl 3-R—NH₂ × HCl 0 — 935A 4 A003394 6 H Cyclohexyl-4-F-Benzyl 3-R—NH₂ × HCl 0 — 936A 5 A003394 6 H 3-Pyridyl-CH₂—4-F-Benzyl 3-R—NH₂ × HCl 0 — 937A 6 A003395 5 H 4-Cl-Benzyl- 4-F-Benzyl3-R—NH₂ × HCl 0 — 756A 7 A003395 5 H 2-Cl-Benzyl- 4-F-Benzyl 3-R—NH₂ ×HCl 0 — 757A 8 A003395 5 H 3-Pyridyl-(CH₂)₂— 4-F-Benzyl 3-R—NH₂ × HCl 0— 758A 9 A003395 5 H 3-Cl-Benzyl- 4-F-Benzyl 3-R—NH₂ × HCl 0 — 760A 10A003401 6 H Cyclopentyl- —CH₂—CH═C(CH₃)₂ 3-R—NH₂ × HCl 0 — 196A 11A003401 6 H 4-F-Phenyl- —CH₂—CH═C(CH₃)₂ 3-R—NH₂ × HCl 0 — 273A 12A003401 6 H 4-F-Phenyl- 4-F-Benzyl 3-R—NH₂ × HCl 0 — 848A

The compounds of formula I of the present invention feature favorableeffects on lipid and carbohydrate metabolism; in particular, they lowerthe blood sugar level and are suitable for the treatment of type IIdiabetes, of insulin resistance, of dislipidemias and of metabolicsyndrome/syndrome X. Moreover, the compounds are suitable for thetreatment and prophylaxis of arteriosclerotic manifestations. Thecompounds can be used alone or in combination with further bloodsugar-lowering active ingredients. The compounds act as DPP IV(dipeptidyl peptidase IV) inhibitors and are also suitable for thetreatment of disorders of perception and other psychiatric indications,for example depressions, anxiety states, anxiety neuroses,schizophrenia, and for the treatment of disorders associated with thecircadian rhythm, for weight reduction in mammals, for the treatment ofimmune disorders and for the treatment of drug abuse. They areadditionally suitable for the treatment of cancer, arthritis,osteoarthritis, osteoporosis, sleep disorders, sleep apnea, masculineand feminine sexual disorders, inflammations, acne, pigmentation of theskin, disorders of steroid metabolism, skin diseases, psoriasis,mycoses, neurodegenerative disorders, multiple sclerosis and Alzheimer'sdisease.

The efficacy of the compounds was tested as follows:

Measurement of the DPP-IV activity:

Material:

DPP-IV from porcine kidneys (Sigma, Munich)

H-Ala-Pro-AFC (Bachem, Weil am Rhein)

Test conditions:

DPP-IV (1 mU/ml, end concentration)

H-Ala-Pro-AFC (15 μm end concentration)

in Tris/HCl (40 mM, pH 7.4), total volume 0.2 ml

The reaction was performed at room temperature for different periods(typically 10 minutes) and stopped at the end of the reaction by adding20 μl of ZnCl₂ (1 M). The conversion of H-AIa-Pro-AFC was determinedfluorimetrically by measuring the emission at 535 nm on excitation at405 nm. In the case of addition of inhibitors, the buffer volume addedwas adjusted such that a total volume of the test mixture of 200 μl wasmaintained.

IC₅₀ values for inhibitors were determined by varying the inhibitorconcentrations at the given substrate concentration of 15 μM. K_(i) andK_(m) values were determined by corresponding variation of substrate andinhibitor concentration as described (Dixon, M. and Webb, E. C. (1979)Enzymes, third edition, pp. 47-206, Academic Press). The values forK_(m), IC₅₀ and K_(i) were calculated using a commercially availablesoftware package (Leatherbarrow, R. J. (1992) GraFit Version 3.0,Erithacus Software Ltd. Staines, U.K.).

TABLE 2 Biological activity of the examples: Example IC₅₀ [μM] 2 1.0 52.5 6 4.3 11 1.8

It can be seen from the table that the compounds of the formula Iinhibit the activity of the DPP-IV (dipeptidyl peptidase IV) and arethus very suitable for lowering the blood sugar level.

The preparation of some working examples will be described in detailhereinafter; the other compounds of the formula I were obtainedanalogously:

Example 1N-(4-Chlorobenzyl)-R-2-(3-aminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxamidehydrochloride a) Methyl 2-hydroxy-1H-benzimidazole-5-carboxylate

The solution of 5.9 g of carbonyldiimidazole in 10 ml ofN-methylpyrrolidone is added dropwise to the solution of 5 g of methyl3,4-diaminobenzoate in 10 ml of N-methylpyrrolidone, and the mixture isheated to 100° C. for 2 hours. After cooling to 60° C., 5 ml of methanolwere added dropwise and then the mixture was stirred at room temperaturewith 150 ml of water, and the precipitate was filtered off with suction,washed with isopropanol and dried under reduced pressure.

Yield: 4.0 g m.p.: 312° C.

b) Methyl 2-chloro-1H-benzimidazole-5-carboxylate

3.9 g of methyl 2-hydroxy-1H-benzimidazole-5-carboxylate and 50 ml ofphosphorus oxychloride are stirred at 10° C. for 6 hours. The resultingthick slurry is, after cooling, stirred cautiously into 500 ml ofice-water, and the solid is filtered off with suction after one hour,washed with water and dried under reduced pressure.

Yield: 4.3 g m.p.: 276° C.

c) Mixture of methyl2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylate and methyl2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole-5-carboxylate

4.3 g of methyl 2-chloro-1H-benzimidazole-6-carboxylate are dissolved in15 ml of N-methylpyrrolidone, admixed with 4.2 g of potash and stirredat room temperature for 60 minutes. 4.86 g of 4-fluorobenzyl bromide arethen added and the mixture is stirred at 70° C. for 4 hours, cooled andstirred with 50 ml of water and 10 ml of glacial acetic acid. The solidis filtered off with suction and dried under reduced pressure.

Yield: 4.0 g m.p. resin

d) Mixture of methylR-2-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylateand methyl2-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-5-carboxylate

The mixture of methyl2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylate and methyl2-chloro-1-(4-fluorobenzyl)-1H-benzimidazole-5-carboxylate (2 g intotal), 15 ml of N-methylpyrrolidone, 3 ml of triethylamine and 2.5 g oftert-butyl R-piperidin-3-ylcarbamate is heated to 100° C. for 6 hours.After being allowed to cool, the mixture is admixed with 50 ml of waterand stirred. The liquid is decanted off from the semi-solid precipitatewhich is taken up again in 5 ml of methanol and precipitated again with30 ml of water and stirred. The solid is filtered off with suction anddried under reduced pressure.

Yield: 2.1 g m.p.: resin

e)R-2-(3-tert-Butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylicacid

The mixture of a total of 2 g ofR-2-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylateand methylR-2-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-5-carboxylatein the solvent mixture of 10 ml of methanol, 20 ml of water and 10 ml oftetrahydrofuran is admixed with 500 mg of lithium hydroxide and stirredat room temperature for 24 hours. After adding 2 ml of glacial aceticacid, the volatile fractions were removed under reduced pressure, theresidue was stirred with water, and the solid was filtered off withsuction and then separated by column chromatography (silica gel, eluent:methylene chloride:isopropanol=94:6), the 5-isomer being eluted first.

Yield: 980 mg m.p.: resin

f) tert-ButylR-{1-[6-(4-chlorobenzylcarbamoyl)-1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-piperidin-3-yl}carbamate(F-34529-074)

The solution of 50 mg ofR-2-(3-tert-butoxycarbonylaminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxylicacid in 1.5 ml of dimethylformamide was admixed successively with 40.6mg of HATU, 18 μl of triethylamine and 14 μl of 4-chlorobenzylamine, andstirred at room temperature overnight. The mixture was then diluted with5 ml of water and the precipitate was filtered off with suction anddried at 40° C. under reduced pressure.

Yield: 30 mg m.p.: resin

g)N-(4-Chlorobenzyl)-R-2-(3-aminopiperidin-1-yl)-1-(4-fluorobenzyl)-1H-benzimidazole-6-carboxamidehydrochloride (F-34529-083)

The solution of 63 mg of tert-butylR-{1-[6-(4-chlorobenzylcarbamoyl)-1-(4-fluorobenzyl)-1H-benzimidazol-2-yl]-piperidin-3-yl}carbamatein 1 ml of ethyl acetate is admixed with 0.2 ml of a saturated HClsolution in ethyl acetate and left to stand at room temperatureovernight. The volatile fractions were removed on a rotary evaporatorand the residue was dissolved in a little methylene chloride andprecipitated with diisopropyl ether. The solid was filtered off withsuction and dried at 40° C. under reduced pressure.

Yield: 15 mg m.p.: 197.1° C.

1. The compound of formula I

wherein R20 is H; R21 is selected from the group consisting of(C₃-C₁₀)-cycloalkyl, (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, phenyl and(C₁-C₆)-alkylene-(C₆-C₁₀)-pyridyl, where the cycloalkyl, aryl andpyridyl radicals are optionally mono- or polysubstituted by F, Cl, Br,I, CN, NO₂, SH, OH, CF₃, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl andS—(C₁-C₆)-alkyl; excluding those definitions of R21 wherein it is anunsubstituted phenyl or unsubstituted benzyl; R3 is selected from thegroup consisting of (C₂-C₁₀)-alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl,where the alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl substituents areoptionally mono- or poly-substituted by F, Cl, Br; R4 and R5 are each H;R11 is selected from the group consisting of H, F, Cl, Br, I,(C₁-C₆)-alkyl, (C₃-C₈)-cycloalkyl, NH₂, NH(C₁-C₆)-alkyl,NH(C₃-C₇)-cycloalkyl, N((C₁-C₆)-alkyl)₂ and O—(C₁-C₆)-alkyl, where thealkyl groups are optionally mono- or poly-substituted by F, Cl, Br or I;and n is 0; or a pharmaceutically acceptable salt thereof.
 2. Thecompound of formula I as recited in claim 1, wherein R20 is H; R21 is(C₃-C₁₀)-cycloalkyl, benzyl, pyridyl and phenyl, where the alkyl,cycloalkyl and benzyl radicals are optionally mono- or polysubstitutedby F, Cl, Br, I, CN, NO₂, SH, OH, (C₁-C₆)-alkyl, O—(C₁-C₆)-alkyl orS—(C₁-C₆)-alkyl; excluding the definitions of unsubstituted phenyl andunsubstituted benzyl from the R21 radical; R3 is selected from the groupconsisting of (C₂-C₁₀)-alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl, wherethe alkenyl and (C₁-C₆)-alkylene-(C₆-C₁₀)-aryl radicals are optionallymono- or polysubstituted by F, Cl, Br; R4 and R5 are each H; R11 isselected from the group consisting of H, F, Cl, Br, I, (C₁-C₆)-alkyl,(C₃-C₈)-cycloalkyl, NH₂, NH(C₁-C₆)-alkyl, NH(C₃-C₇)-cycloalkyl,N((C₁-C₆)-alkyl)₂ and O—(C₁-C₆)-alkyl, where the alkyl groups areoptionally mono- or poly-substituted by F, Cl, Br or I; n is 0; or apharmaceutically acceptable salt thereof.